Claims:WE CLAIM:

1. A modified release solid oral dosage formulation comprising:

a) core particle comprising Dexlansoprazole and one or more pharmaceutically acceptable excipients, coated with a matrix of pH independent soluble or swellable polymer or mixture of pH dependent soluble or swellable polymer or mixture of polymers designed to release about 10% - 35% of the Dexlansoprazole at a pH of 5.0 to 6.0, and release the remaining 90% - 65% of the Dexlansoprazole at a pH in the range of 6.0 to 7.5 and

b) one or more pharmaceutical excipients.

2. A modified release solid oral dosage formulation of Dexlansoprazole comprising
a) core particle comprising Dexlansoprazole and one or more pharmaceutically acceptable excipients, coated with a matrix of pH independent soluble or swellable polymer or mixture of pH dependent soluble or swellable polymer or mixture of polymers designed to release about 90% - 65% of the Dexlansoprazole at a pH of 5.0 to 6.0, and release the remaining 10% - 35% of the Dexlansoprazole at a pH in the range of 6.0 to 7.5 and
b) one or more pharmaceutical excipients.

3. The dosage form according to claims 1 and 2, wherein one more pharmaceutically acceptable excipients are selected from diluents, binder, disintegrant, glidants, lubricant and alkalizing agent.

4. The dosage form according to claims 1 and 2, wherein the core particle is selected from granules, spheroids, tablets, mini tablets or pellets.

5. The dosage form according to claim 3, wherein pellet is selected from sugar spheres, microcrystalline cellulose spheres, silicon dioxide spheres, glass spheres, polypropylene spheres and corn starch spheres, or a combination thereof.

6. The dosage form according to claims 1 and 2, wherein the pH independent polymer is selected from Hydroxypropylmethylcellulose, ethylcellulose, Hydroxypropylcellulose, sodium alginate, pectin, carrageenan, polyethylene glycol, povidone, polyvinyl acetate, polyethylene oxides, sodium starch glycolate, Veegum, Hydroxy ethylcellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, starches, modified starches, croscarmellose sodium, gelatin, polysaccharides, resins, waxes and fatty substances.

7. The dosage form according to claims 1 and 2, wherein the pH independent polymer is selected from Hydroxypropylmethylcellulose phthalate Hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, methyl methacrylate copolymer, carbomer.

8. The dosage form according to claim 7, wherein the amount of pH dependent polymer range from about 5% to about 50% based on the fill weight of the capsule or final tablet weight.

9. The dosage form according to claims 1 and 2, wherein the core comprising Dexlansoprazole in composition is coated with seal coat composition comprising a mixture of hydrophilic and hydrophobic polymers. Hydrophilic polymer such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose and hydrophobic polymer such as ethylcellulose, polyvinyl acetate, Hydroxy ethylcellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, resins, waxes and fatty substances or mixtures thereof.

10. The dosage form according to claims 1 and 2, wherein core particle comprising Dexlansoprazole coated with seal coat comprising a mixture of hydrophilic and hydrophobic polymers.

11. The dosage form according to claim 10, wherein the seal further comprises an alkalizer and anti-tacking agent.

12. The dosage form according to claim 3, wherein diluent is selected from lactose, sucrose, calcium phosphate, calcium sulfate, microcrystalline cellulose, mannitol, starch, pregelatinized starch, sorbitol, magnesium oxide, Sodium chloride and the like or combination thereof.

13. The dosage form according to claim 3, wherein binder is selected from polyvinylpyrrolidone, xanthan gum, Carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low substituted hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, Pregelatinized starch and the like or mixture thereof.

14. The dosage form according to claim 3, wherein disintegrant is selected from crospovidone, croscarmellose sodium, sodium starch glycolate, carmellose calcium and the like or mixture thereof.

15. The dosage form according to claim 3, wherein the alkalizing agent is selected from carbonate or bicarbonates of calcium, potassium, sodium and magnesium, sodium Hydroxide, sodium phosphate and the like.

16. In yet another embodiment, the core comprising Dexlansoprazole may be prepared by the process comprising the steps of:
(i) granulating Dexlansoprazole, diluent selected from lactose, microcrystalline cellulose; disintegrant selected from sodium starch glycolate, croscarmellose sodium; alkalizing agent selected from heavy magnesium carbonate, calcium carbonate using aqueous or non-aqueous binder solution,
(ii) drying the granules of step (i) and
(iii) blending the dried granules of step (ii) with extra granular excipients selected from diluent selected from lactose, microcrystalline cellulose; disintegrant selected from sodium starch glycolate, croscarmellose sodium; and lubricant selected from magnesium stearate and sodium stearyl fumarate and
(iv) Compressing the blend of step (iii) into tablets/mini tablets.

17. In a preferred embodiment, the modified release solid oral dosage formulation according to present invention comprises:

i) core pellets comprising

a) Dexlansoprazole
b) a seal coat applied on the core pellets comprising
c) a mixture of hydrophilic selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydrophobic polymer selected from ethylcellulose, polyvinyl acetate, Hydroxy ethylcellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, resins, waxes and fatty substances or mixtures thereof and
d) an alkalizer and
e) an anti-tacking agent

ii) polymer coat comprising a matrix of pH- independent soluble or swellable polymer or mixture of pH-dependent soluble or swellable polymer or mixture of pH independent and pH dependent polymer, wherein the pH independent polymer is selected from hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, sodium alginate, pectin, carrageenan, polyethylene glycol, povidone, polyvinyl acetate, polyethylene oxides, sodium starch glycolate, Veegum, Hydroxy ethylcellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, starches, modified starches, croscarmellose sodium, gelatin, polysaccharides, resins, waxes and fatty substances and the pH dependent polymer is selected from hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, methyl methacrylate copolymer, carbomer and the like,

iii) and one more pharmaceutically acceptable excipient are selected from diluents, binder, disintegrant, glidants, lubricant and alkalizing agent.

18. A modified release capsule dosage form comprising:

a) Inert pellets

b) active layer comprising Dexlansoprazole; one or more diluent selected from lactose or microcrystalline cellulose or mixture thereof; disintegrant selected from sodium starch glycolate, croscarmellose sodium; alkalizing agent selected from magnesium carbonate, calcium carbonate and lubricant selected from magnesium stearate and sodium stearyl fumarate;

c) a seal coat on the active core comprising i) a mixture of hydrophilic selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydrophobic polymer selected from ethylcellulose, polyvinyl acetate, Hydroxy ethylcellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, resins, waxes and fatty substances or mixtures thereof; ii) triethyl citrate and iii) talc

d) polymer coat on seal coated pellets comprising a matrix of pH- independent soluble or swellable polymer or mixture of pH-dependent soluble or swellable polymer or mixture of pH independent and pH dependent polymer, wherein the pH independent polymer is selected from Hydroxypropylmethylcellulose, ethylcellulose, Hydroxypropylcellulose, sodium alginate, pectin, carrageenan, polyethylene glycol, povidone, polyvinyl acetate, polyethylene oxides, sodium starch glycolate, Veegum, Hydroxyethyl cellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, starches, modified starches, croscarmellose sodium, gelatin, polysaccharides, resins, waxes and fatty substances and the pH dependent polymer is selected from Hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, methyl methacrylate copolymer, carbomer.
, Description:FIELD OF THE INVENTION

The technical field of the present invention relates to modified release formulations of proton pump inhibitors. More particularly, the present invention relates to modified release formulations of Dexlansoprazole. The present invention also relates to the process for the preparation of modified release formulations of Dexlansoprazole.

BACKGROUND OF THE INVENTION

Dexlansoprazole is a proton pump inhibitor (PPI) indicated for healing of all grades of erosive esophagitis (EE) and gastro esophageal reflux disease (GERD). Chemically it is (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl] methyl} sulfinyl]-/H-benzimidazole. Commercially it is available under the trade name Dexilant in the US as delayed release capsules. Commercially available capsules are formulated as dual release formulation containing Dexlansoprazole in a mixture of two types of enteric-coated granules with different pH-dependent dissolution profiles. Dexilant capsules are available in two dosage strengths: 30 mg and 60 mg, per capsule. Each capsule contains enteric-coated granules consisting of Dexlansoprazole (active ingredient) and the following inactive ingredients: sugar spheres, magnesium carbonate, sucrose, low-substituted hydroxypropyl cellulose, titanium dioxide, hydroxypropyl cellulose, hypromellose 2910, talc, methacrylic acid copolymers, polyethylene glycol 8000, triethyl citrate, polysorbate 80, and colloidal silicon dioxide.

US Patent No. 7,790,755 discloses a capsule comprising composition(i) comprising a tablet, granule or fine granule in which a release of an active ingredient is controlled; said tablet, granule or fine granule comprising a core particle containing Dexlansoprazole, and a pH-dependently soluble release-controlled coating-layer which comprises one kind of polymeric substance or a mixture of two or more kinds of polymeric substances having different release properties selected from the group consisting of hydroxypropylmethyl] cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methy] methacrylate copolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate and shellac; said polymeric substance is soluble in the pH range of 6.0 to 7.5, and composition (ii) comprising a tablet, granule or fine granule comprising a core particle containing the active ingredient and enteric coat such that the active ingredient is released in the pH range of no less than 5.0 to no more than 6.0.

The prior art discloses the use of two different pH dependent enteric coated granules to delay the release of the drug. However, the in-vivo release of the active ingredient from such a formulation especially the portion of the drug desired to be released in the pH range of 5.0 — 6.0 would be highly variable as it depends to a great extent on the pH in the gastrointestinal tract which in turn is dependent on factors such as fed/fasted state, type of food taken, gastric acidosis or alkalosis and concomitant administration of other pH altering medication or food substances. Such variabilities could lead to dose-dumping or no or insufficient release.

To avoid such variabilities in drug release, the inventors of the present invention have developed controlled release formulation of Dexlansoprazole in such a way that the drug release in the pH range of no less than 5.0 to no more than 6.0 is controlled with the use of pH-independently soluble and/or swellable polymer or polymer mixture and that in the pH range of no less than 6.0 to no more than 7.5 is controlled with the use of pH-dependently soluble and/or swellable polymer or polymer mixture.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a novel, simple, economic, cost effective and industrially feasible process for the preparation of Methyl-4-methoxyacetoacetate.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a modified release solid oral dosage formulation comprising:

a) core particle comprising Dexlansoprazole and one or more pharmaceutically acceptable excipients, coated with a matrix of pH independent soluble or swellable polymer or mixture of pH dependent soluble or swellable polymer or mixture of polymers designed to release about 10% - 35% of the Dexlansoprazole at a pH of 5.0 to 6.0, and release the remaining 90% - 65% of the Dexlansoprazole at a pH in the range of 6.0 to 7.5 and
b) One or more pharmaceutical excipients.

In another aspect, the present invention provides a modified release solid oral dosage formulation of Dexlansoprazole comprising:

a) core particle comprising Dexlansoprazole and one or more pharmaceutically acceptable excipients, coated with a matrix of pH independent soluble or swellable polymer or mixture of pH dependent soluble or swellable polymer or mixture of polymers designed to release about 90% - 65% of the Dexlansoprazole at a pH of 5.0 to 6.0, and release the remaining 10% - 35% of the Dexlansoprazole at a pH in the range of 6.0 to 7.5 and
b) One or more pharmaceutical excipients.

Figure of the invention

Fig 1: Diagrammatic depiction of the composition according to the invention

DETAILED DESCRIPTION OF THE INVENTION

In another embodiment the core particle includes granules, spheroids, tablets, mini tablets, pellets and the like.

In another embodiment one more pharmaceutically acceptable excipients are selected from diluents, binder, disintegrant, glidants, lubricant and alkalizing agent.

In one aspect, pellets include sugar spheres, microcrystalline cellulose spheres, silicon dioxide spheres, glass spheres, polypropylene spheres and corn starch spheres, or a combination thereof.

In one aspect, the capsule is a gelatin capsule or HPMC capsule and the tablet is orally disintegrating tablet or conventional tablet.

In one aspect, the core particle comprises comprising Dexlansoprazole and one or more pharmaceutically acceptable excipients, coated with mixture of polymers designed to release about 10% - 35% of the Dexlansoprazole in the pH range of no less than 5.0 to no more than 6.0, and release the remaining 90% - 65% of the Dexlansoprazole in the pH range of no less than 6.0 to no more than 7.5.

In one aspect, the core particle comprises comprising Dexlansoprazole and one or more pharmaceutically acceptable excipients, coated with mixture of polymers designed to release about 90% - 65% of Dexlansoprazole in the pH range of no less than 5.0 to no more than 6.0, and release the remaining10% - 35% of Dexlansoprazole in the pH range of no less than 6.0 to no more than 7.5.

The pH independent polymer according to present invention may be selected from hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropyl cellulose, sodium alginate, pectin, carrageenan, polyethylene glycol, povidone, polyvinyl acetate, polyethylene oxides, sodium starch glycolate, Veegum, Hydroxyethyl cellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, starches, modified starches, croscarmellose sodium, gelatin, polysaccharides, resins, waxes and fatty substances and the like. The amount of pH independent soluble polymer used may range from about 0.5% to about 30% based on the fill weight of the capsule or final tablet weight.

The pH dependent polymer according to present invention may be selected from hydroxypropylmethyl cellulose phthalate hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, methyl methacrylate copolymer, carbomer and the like. The amount of pH dependent polymer may range from about 5% to about 50% based on the fill weight of the capsule or final tablet weight.

The core comprising Dexlansoprazole in composition may optionally be coated with seal coat composition comprising a mixture of hydrophilic and hydrophobic polymers. Hydrophilic polymer such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydrophobic polymer such as ethylcellulose, polyvinyl acetate, Hydroxyethyl cellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, resins, waxes and fatty substances and the like or mixtures thereof may be used for seal coating the core. The seal coat composition may further comprise an alkalizer and anti-tacking agent.

The seal coating over the core provides a protective coat effectively separating the Dexlansoprazole from enteric coating polymer coat with which it is incompatible and also provides durable cores for further coating especially for granules, pellets or spheroids in fluid bed process (Wurster process).

Suitable diluents used according to present invention are selected from lactose, sucrose, calcium phosphate, calcium sulfate, microcrystalline cellulose, mannitol, starch, pregelatinised starch, sorbitol, magnesium oxide, Sodium chloride and the like or combination thereof. The amount of diluent may range from about 5% to about 70% based on the fill weight of the capsule or final tablet weight.

Suitable binder of the present invention includes polyvinylpyrrolidone, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low substituted hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, Pregelatinized starch and the like or mixture thereof. The amount of binder may range from about 1% to about 50% based on the fill weight of the capsule or final tablet weight.

Suitable disintegrants used according to present invention are selected from crospovidone, croscarmellose sodium, sodium starch glycolate, carmellose calcium and the like or mixture thereof. The amount of disintegrant may range from about 0% to about 20% based on the fill weight of the capsule or final tablet weight.

Suitable glidants of the present may be selected from calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, talc, silicon dioxide and the like.

The alkalizing agent of the present invention may be selected from carbonate or bicarbonates of calcium, potassium, sodium and magnesium, sodium Hydroxide, sodium phosphate and the like.

Suitable lubricants of the present invention include sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate and the like or mixture thereof.

In another aspect, the present invention provides a modified release formulation of a proton pump inhibitor comprising of
Composition (i) Comprising
Core particle, granule, spheroid, tablet/mini tablet or pellet containing 10% - 35% of the label claim of Dexlansoprazole and one or more pharmaceutically acceptable excipients, coated with and/or dispersed in a matrix of pH- independently soluble and /or swellable polymer or mixture of polymers designed to release about 10% - 35% of the label claimed active drug substance in the pH range of no less than 5.0 to no more than 6.0, and
Composition (ii) comprising
Core particle, granule, spheroid, tablet/mini tablet or pellet containing the remaining 90% - 65% of the label claim of Dexlansoprazole and one or more pharmaceutically acceptable excipients, seal coated with and/or dispersed in a matrix of pH-independently soluble and /or swellable polymer or mixture of polymers and further coated with and/or dispersed in a matrix of pH- dependently soluble and /or swellable polymer or mixture of polymers designed to release the remaining 90% - 65% of the label claimed active drug substance in the pH range of no less than 6.0 to no more than 7.5. or vice-versa and optionally containing additional pharmaceutical additives/excipients required for processing the said modified release formulation into the dosage form for administration.

In another aspect, the present invention provides a modified release solid oral dosage formulation of Dexlansoprazole comprising
a) core particle comprising
i. Dexlansoprazole and one or more pharmaceutically acceptable excipients,
ii. coated with a matrix of pH independent soluble or swellable polymer or mixture of pH dependent soluble or swellable polymer or mixture of polymers designed to release about 90% - 65% of the Dexlansoprazole at a pH of 5.0 to 6.0, and release the remaining 10% - 35% of the Dexlansoprazole at a pH in the range of 6.0 to 7.5 and
b) one or more pharmaceutical excipients.

In another aspect, the present invention provides a modified release solid oral dosage formulation of Dexlansoprazole comprising
a) core particle comprising
i. Dexlansoprazole and one or more pharmaceutically acceptable excipients,
ii. coated with a matrix of pH independent soluble or swellable polymer or mixture of pH dependent soluble or swellable polymer or mixture of polymers designed to release about 10% - 35% of Dexlansoprazole at a pH of 5.0 to 6.0, and release the remaining 90% - 65% of Dexlansoprazole at a pH in the range of 6.0 to 7.5 and
b) one or more pharmaceutical excipients.

In another embodiment, the core comprising Dexlansoprazole may be prepared by the process comprising the steps of:
(i) granulating Dexlansoprazole and an alkalizing agent with one or more excipients comprising of diluent, disintegrant, alkalizing agent using aqueous or non-aqueous binder solution,
(ii) drying the granules of step (i) and
(iii) blending the dried granules of step (ii) with extra granular excipients comprising of diluents, disintegrant and lubricant, and
(iv) compressing the blend of step (iii) into tablets/mini tablets.

In yet another embodiment, the core comprising Dexlansoprazole may be prepared by the process comprising the steps of:
(i) granulating Dexlansoprazole, diluent selected from lactose, microcrystalline cellulose; disintegrant selected from sodium starch glycolate, croscarmellose sodium; alkalizing agent selected from heavy magnesium carbonate, calcium carbonate using aqueous or non-aqueous binder solution,
(ii) drying the granules of step (i) and
(iii) blending the dried granules of step (ii) with extra granular excipients selected from diluent selected from lactose, microcrystalline cellulose; disintegrant selected from sodium starch glycolate, croscarmellose sodium; and lubricant selected from magnesium stearate and sodium stearyl fumarate and
(iv) compressing the blend of step (iii) into tablets/mini tablets.

In a preferred embodiment, the modified release solid oral dosage formulation according to present invention comprises:
1) core pellets comprising
a) Dexlansoprazole
b) a seal coat applied on the core pellets comprising
i. a mixture of hydrophilic selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydrophobic polymer selected from ethylcellulose, polyvinyl acetate, Hydroxyethyl cellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, resins, waxes and fatty substances and the like or mixtures thereof and
ii. an alkalizer and
iii. an anti-tacking agent
c) polymer coat comprising a matrix of pH- independent soluble or swellable polymer or mixture of pH-dependent soluble or swellable polymer or mixture of pH independent and pH dependent polymer, wherein the pH independent polymer is selected from Hydroxypropylmethylcellulose, ethylcellulose, Hydroxypropylcellulose, sodium alginate, pectin, carrageenan, polyethylene glycol, povidone, polyvinyl acetate, polyethylene oxides, sodium starch glycolate, Veegum, Hydroxyethyl cellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, starches, modified starches, croscarmellose sodium, gelatin, polysaccharides, resins, waxes and fatty substances and the pH dependent polymer is selected from hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, methyl methacrylate copolymer, carbomer and the like,
2) and one more pharmaceutically acceptable excipients are selected from diluents, binder, disintegrant, glidants, lubricant and alkalizing agent.

In one aspect, the core particle, granule, spheroid, tablet/mini tablet or pellet containing Dexlansoprazole is manufactured by processing Dexlansoprazole with one or more pharmaceutically acceptable excipients using techniques such as granulation, roll-compaction, slugging, extrusion-spheronization and compression.

In yet another aspect, the core particle, granule, spheroid, tablet/mini tablet or pellet containing Dexlansoprazole is manufactured by depositing Dexlansoprazole or a mixture of Dexlansoprazole and a binder on an inert core with or without an intervening adhesive layer by coating, layering or dusting.

The coating according to the present invention is applied by dissolving/dispersing the polymer, plasticizer and anti-tacking agent in solvents such as isopropyl alcohol, acetone, water, ethanol, methylene chloride and the like or mixtures thereof.

Suitable plasticizers used according to present invention are selected from diethylphthalte, dibutylphthalate, cetyl alcohol, polyethylene glycol, triethyl citrate, Triacetin, propylene glycol and the like.

Suitable anti-tacking agents used according to present invention are selected from talc, magnesium stearate and the like or mixture thereof.

In another embodiment, the composition is compressed together into a tablet or more preferably encapsulated together in an empty hard gelatin capsule.

In one aspect, the present invention provides a modified release tablet dosage form comprising:

a) tablet core comprising Dexlansoprazole, diluent selected from lactose, microcrystalline cellulose; disintegrant selected from sodium starch glycolate, croscarmellose sodium; alkalizing agent selected from magnesium carbonate, calcium carbonate and lubricant selected from magnesium stearate and sodium stearyl fumarate;

b) a seal coat on the tablet core comprising a mixture of hydrophilic selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydrophobic polymer selected from ethylcellulose, polyvinyl acetate, Hydroxyethyl cellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, resins, waxes and fatty substancesand the like or mixtures thereof; Triethyl citrate and talc

c) polymer coat on seal coated tablet core comprising a matrix of pH- independent soluble or swellable polymer or mixture of pH-dependent soluble or swellable polymer or mixture of pH independent and pH dependent polymer, wherein the pH independent polymer is selected from Hydroxypropylmethylcellulose, ethylcellulose, Hydroxypropylcellulose, sodium alginate, pectin, carrageenan, polyethylene glycol, povidone, polyvinyl acetate, polyethylene oxides, sodium starch glycolate, Veegum, Hydroxy ethylcellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, starches, modified starches, croscarmellose sodium, gelatin, polysaccharides, resins, waxes and fatty substances and the pH dependent polymer is selected from Hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, methyl methacrylate copolymer, carbomer and the like.

In one aspect, the present invention provides a modified release capsule dosage form comprising:

a) Inert pellets
b) Active layer comprising Dexlansoprazole; one or more diluent selected from lactose or microcrystalline cellulose or mixture thereof; disintegrant selected from sodium starch glycolate, croscarmellose sodium; alkalizing agent selected from magnesium carbonate, calcium carbonate and lubricant selected from magnesium stearate and sodium stearyl fumarate;
c) a seal coat on the active core comprising i) a mixture of hydrophilic selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydrophobic polymer selected from ethylcellulose, polyvinyl acetate, Hydroxyethyl cellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, resins, waxes and fatty substances and the like or mixtures thereof; ii) triethyl citrate and iii) talc
d) polymer coat on seal coated pellets comprising a matrix of pH- independent soluble or swellable polymer or mixture of pH-dependent soluble or swellable polymer or mixture of pH independent and pH dependent polymer, wherein the pH independent polymer is selected from Hydroxypropylmethylcellulose, ethylcellulose, Hydroxypropylcellulose, sodium alginate, pectin, carrageenan, polyethylene glycol, povidone, polyvinyl acetate, polyethylene oxides, sodium starch glycolate, Veegum, Hydroxyethyl cellulose, Eudragit RL PO, Eudragit RS PO, Eudragit NE 30D, Eudragit NE 40D, starches, modified starches, croscarmellose sodium, gelatin, polysaccharides, resins, waxes and fatty substances and the pH dependent polymer is selected from Hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, methyl methacrylate copolymer, carbomer and the like.

In another embodiment, the present invention provides a method of treating erosive esophagitis (EE) and gastro esophageal reflux disease (GERD), which comprises administering an effective amount of controlled release oral solid dosage form of the present invention to a patient in need thereof.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the compositions for other dosage forms and substitute the equivalent excipients as described in the specification or with the one known to the industry.

EXAMPLE 1: DEXLANSOPRAZOLE DELAYED RELEASE CAPSULE 60MG (TABLETS IN CAPSULE)

S.No Ingredients mg /Cap
1 Dexlansoprazole 12.00
2 Light magnesium carbonate 5.00
3 Lactose monohydrate 20.60
4 Sodium starch glycolate 1.00
5 Hydroxypropyl methyl cellulose 1.20
6 Purified water Qs
7 Magnesium stearate 0.20
Core Weight 40.00
Coating I
8 Hydroxypropyl methyl cellulose 4.00
9 Ethylcellulose 2.00
10 Talc 1.00
11 Triethyl citrate 1.00
12 Purified water Qs
13 Ethyl alcohol Q.s
Coating II
14 Eudragit S 100 7.000
15 Ethylcellulose 4.00
16 Triethyl citrate 0.800
17 Talc 0.200
18 Purified water Qs
19 Ethyl alcohol qs

Tablet weight 60.00
Capsule filling
Size “1” EHG Capsule 5 tablets per capsules

The processing steps involved in manufacturing of Dexlansoprazole given in example 1 are given below:
i) Dexlansoprazole, light magnesium carbonate, lactose, sodium starch glycolate were sifted and blended,
ii) granulated the blended material of step (i) with a solution of hydroxypropyl methyl cellulose in water,
iii) dried and sifted the granules obtained in step (ii), through the required size mesh,
iv) lubricated the granules of step (iii) with magnesium stearate and
v) compressing the lubricated granules of step (iv)into tablets
vi) preparing the solution / dispersion of hydroxypropylmethyl cellulose, ethylcellulose, triethyl citrate and talc in Ethanol and purified water,
vii) coating the solution of step (vi) onto tablets of step (v)
viii) preparing the solution / dispersion of Eudragit S 100, Ethylcellulose, triethyl citrate and talc in Ethanol and purified water, and
ix) Coating the solution of step (viii) onto the coated tablets of step (vii) and
x) Finally filling the coated mini tablets in an empty hard gelatin capsule.

EXAMPLE 2: DEXLANSOPRAZOLE DELAYED RELEASE CAPSULE 60MG (PELLETS FILLED IN CAPSULE)

S.No Ingredients mg /Cap
1 Dexlansoprazole 60.00
2 Light magnesium carbonate 25.00
3 Microcrystalline cellulose 75.00
4 Hydroxypropyl methyl cellulose 10.00
5 Purified water Qs
Core Weight 170.00
Coating I
6 Hydroxypropyl methyl cellulose 30.00
7 Ethylcellulose 10.00
8 Talc 2.000
9 Triethyl citrate 3.00
10 Purified water Qs
11 Ethyl alcohol Q.s
Coating II
12 Eudragit S 100 60.000
13 Ethylcellulose 14.00
14 Triethyl citrate 8.00
15 Talc 3.000
16 Purified water Qs
17 Ethylalcohol qs

The processing steps involved in manufacturing of Dexlansoprazole given in example 2 are given below:
i) Sifting and blending Dexlansoprazole, microcrystalline cellulose, magnesium carbonate and HPMC,
ii) granulating the blended material of step (i) with water,
iii) Extruding the wet mass through 1.0 mm screen in an extruder, the resultant extrudates spheronized, dried and sized to obtain pellets of uniform desired size.
iv) preparing the solution / dispersion of hydroxypropylmethyl cellulose, Ethylcellulose, triethyl citrate and talc in ethyl alcohol and purified water,
v) coating the solution of step (iv) onto pellets of step (iii),
vi) preparing the solution / dispersion of Eudragit S 100, ethylcellulose, triethyl citrate and talc in ethyl alcohol and purified water, and
vii) coating the solution of step (vi) onto the coated pellets of step (v),
viii) Finally filling the pellets in an empty hard gelatin capsule or compressed in to tablets (MUPS)

DEXLANSOPRAZOLE DELAYED RELEASE CAPSULE 60MG (TABLETS FILLED IN CAPSULE)

S. No. Ingredients Mg / Tablet
1. Enteric coated pellets of Example 2 300.00
2. Lactose Monohydrate 150.00
3. L- HPC LH 11 25.00
4. Sodium Starch Glycolate 25.00
5. Microcrystalline cellulose 90.00
6. Magnesium Stearate 10.00
7. Tablet Weight 600.00

EXAMPLE 3: DEXLANSOPRAZOLE DELAYED RELEASE CAPSULE 60MG (PELLETS FILLED IN CAPSULE)

S.No Ingredients mg /Cap
1 Dexlansoprazole 60.00
2 Light magnesium carbonate 25.00
3 Sucrose powder 30.00
4 Sugar spheres 45.00
5 Hydroxypropyl methyl cellulose 20.00
6 Purified water Qs
Core Weight 180.00
Coating I
7 Hydroxypropyl methyl cellulose 30.00
8 Ethylcellulose 10.00
9 Talc 2.000
10 Triethyl citrate 3.00
11 Purified water Qs
12 Ethyl alcohol Q.s
Coating II
13 Eudragit S 100 60.000
14 Ethylcellulose 14.00
15 Triethyl citrate 8.00
16 Talc 3.000
17 Purified water Qs
18 Ethyl alcohol qs

The processing steps involved in manufacturing of Dexlansoprazole given in example 2 are given below:
i) Preparing the aqueous solution / dispersion of hydroxypropylmethyl cellulose, Dexlansoprazole, magnesium carbonate, and sucrose powder with purified water,
ii) Drug loading on to the sugar spheres using the drug suspension of step (i) ,
iii) preparing the solution / dispersion of hydroxypropylmethyl cellulose, Ethylcellulose, triethyl citrate and talc in ethyl alcohol and purified water,
iv) coating the solution of step (iv) onto pellets of step (iii),
v) preparing the solution / dispersion of Eudragit S 100, ethylcellulose, triethyl citrate and talc in ethyl alcohol and purified water, and
vi) coating the solution of step (vi) onto the coated pellets of step (v) and
vii) Finally filling the pellets in an empty hard gelatin capsule or compressed in to tablets (MUPS)

1 Capsule filling Mg /Capsule
Pellets weight per each capsule (Size 1) 310.00

EXAMPLE 4: DEXLANSOPRAZOLE DELAYED RELEASE CAPSULE 60MG (PELLETS FILLED IN CAPSULE)
Composition 1:
S.No Ingredients mg /Cap
1 Dexlansoprazole 15.000
2 Sodium Chloride 26.000
3 Microcrystalline cellulose 10.000
4 Sodium starch glycolate 5.000
5 Low substituted hydroxypropyl cellulose 11.000
6 Purified water Qs
Core Weight 67.000
Coating I
7 Hydroxypropyl methyl cellulose 20.000
8 Talc 2.000
9 Purified water Qs
Coating II
10 Hydroxypropyl methyl cellulose (HPMC E-50 LV) 10.000
11 Talc 0.100
12 Purified water Qs

The processing steps involved in manufacturing composition (1) of Dexlansoprazole given in example 2 are given below:
i) Sifting and blending Dexlansoprazole, microcrystalline cellulose, sodium starch glycolate and low substituted hydroxypropyl cellulose,
ii) granulating the blended material of step (i) with a solution of sodium chloride in water,
iii) | Extruding the wet mass through 1.0 mm screen in an extruder, the resultant extrudates spheronized, dried and sized to obtain pellets of uniform desired size.
iv) preparing the aqueous solution / dispersion of hydroxypropylmethyl cellulose and talc in purified water,
v) coating the solution of step (iv) onto pellets of step (iii),
vi) preparing the aqueous solution / dispersion of hydroxypropylmethyl cellulose and talc in purified water, and
vii) coating the solution of step (vi) onto the coated pellets of step (v).
Composition 2:
S.No Ingredients mg /Cap
1 Dexlansoprazole 45.000
2 Heavy magnesium carbonate 75.000
3 Microcrystalline cellulose 60.000
4 Low substituted hydroxypropyl cellulose 27.000
5 Magnesium Stearate 3.000
6 Purified water Qs
Core Weight 210.000
Coating I
7 Hydroxypropyl methyl cellulose 21.000
8 Talc 2.000
9 Purified water Qs
Coating II
10 Eudragit S 100 40.775
11 Iron oxide Red 0.100
12 Triethyl Citrate 6.125
13 Isopropyl Alcohol Qs

The processing steps involved in manufacturing composition (2) of Dexlansoprazole
given in example 2 are given below:
i) Sifting and blending Dexlansoprazole, heavy magnesium carbonate, microcrystalline cellulose,
ii) granulating the blended material of step (i) with a solution of low substituted hydroxypropyl cellulose in water,
iii) Extruding the wet mass through 1.0 mm screen in an extruder, the resultant extrudates spheronized, dried and sized to obtain pellets of uniform desired size.,
iv) preparing the aqueous solution / dispersion of hydroxypropylmethyl cellulose and talc in purified water,
v) coating the solution of step (iv) onto pellets of step (iii),
vi) preparing the dispersion of Eudragit, iron oxide red and triethyl citrate in acetone and isopropyl alcohol,
vii) coating the solution of step (vi) onto coated pellets of step (v)
S.No Ingredients mg /Cap
1 Composition 1 100(1tabX 100 mg)
2 Composition 2 280(4 mini tabs X 70 mg)
Fill Weight 380.000
3 Empty Hard gelatin capsule ‘’1” 1 No.

Finally blending the pellets of composition (1) and composition (2) and filling in an empty hard gelatin capsule.

DISSOLUTION PROFILE:

The dissolution of the Delayed Release Capsule of Dexlansoprazole prepared in above examples was carried out in USP apparatus -1, at 100rmp. Samples were collected at different time intervals and found to be comparable with reference listed product. The dissolution profile is given table below:

TABLE – 1 COMPARISON OF DISSOLUTION BETWEEN THE REFERENCE AND TEST PRODUCTS

Medium 500ml 0.1N HCI; Basket 100rpm; 2hrs
DEXILANT Example 1 Example 2 Example 3 Example 4
TIME (Mins.) Average
(% Dissolved) Average
(% Dissolved) Average
(% Dissolved) Average
(% Dissolved) Average
(% Dissolved)
120 0 0 0 2 1
followed by 900ml pH 5.5 with 5mM SLS; Basket 100rpm
DEXILANT Example 1 Example 2 Example 3 Example 4
TIME (Mins.) Average
(% Dissolved) Average
(% Dissolved) Average
(% Dissolved) Average
(% Dissolved) Average
(% Dissolved)
15 8 11 8 9 10
30 14 17 12 15 16
60 23 28 25 23 24
Followed by 900m! pH 7.0 with 5mM SLS; Basket 100rpm
DEXILANT Example 1 Example 2 Example 3 Example 4
TIME (Mins.) Average
(% Dissolved) Average
(% Dissolved) Average
(% Dissolved) Average
(% Dissolved) Average
(% Dissolved)
10 32 35 38 30 31
15 40 46 43 39 37
30 48 55 50 48 46
45 58 63 59 55 55
60 65 70 74 68 67
75 75 79 83 80 81
105 92 95 94 91 90
120 97 95 94 97 97